Capsules are well-known dosage forms that normally consist of a shell filled with one or more specific substances. The shell may be a soft or a hard stable shell comprising film-forming polymer(s) such as gelatin, modified starches or modified celluloses. Hard capsules are generally manufactured by using a dip molding process. In this process, pin molds are dipped into a film forming composition. By gelling the film forming polymer on the pin, a film is formed that is subsequently dried on the pin to obtain a capsule shell. The shells are then stripped off the pins and cut to a desired length. Thus, capsules caps and bodies are obtained that can later be filled with a substance and joined such that a filled capsule is obtained. When using this type of dip molding process, it is necessary to ensure that the dipping composition adheres to the pin surface and quickly gels, once the pins are withdrawn from the dipping bath. This avoids that the composition flows on the pins surface so as to achieve the desired shell or film thickness distribution to manufacture capsules. When using gelatin as the film forming polymer, the dipping compositions gel with cooling. The same gelling behavior is shown by mixtures of methyl celluloses and gelling agents. Both these types of film forming polymers may be processed on conventional devices for manufacturing hard gelatin capsules. Methylcellulose and hydroxypropyl methylcellulose have “thermoreversible gelation properties”. Described specifically, when an aqueous solution of methylcellulose or hydroxypropyl methylcellulose is heated, de-hydration of the hydrophobic methoxyl groups localized in the molecule occurs and it turns into a hydrous gel. When the resulting gel is cooled, on the other hand, the hydrophobic methoxyl groups are re-hydrated, whereby the gel returns to the original aqueous solution.
U.S. Pat. No. 2,526,683 discloses a process for preparing methyl cellulose medicinal capsules by a dip coating process. The process consists of dipping a capsule forming pin pre-heated to 40° C.-85° C. into a methyl cellulose composition maintained at a temperature below the temperature where gelation begins, withdrawing the pins and placing the pins in ovens at temperatures above the gelation temperature and drying the film. When the hot pins are dipped into the composition, the composition gels on the surface of the pin and as the pin is withdrawn, a film of gelled liquid of a certain thickness is formed on the pin. The pin is typically placed in the oven to dry. This technique is conventionally named “thermogelation”. The dry capsule is then stripped, cut to size and the body and caps are fitted together.
Due to the thermoreversible gelation properties of methylcellulose and hydroxypropyl methylcellulose, these cellulose ethers have also been suggested as film-forming coatings on dosage forms, such as tablets, granules, pellets, caplets, lozenges, suppositories, pessaries or implantable dosage forms. However, methyl cellulose is quite hydrophobic; its hydrophobic properties are not compatible with some of the common capsule ingredients or fillings. Moreover, for some applications, capsules made from methyl cellulose do not dissolve fast enough in water.
U.S. Pat. No. 3,493,407, discloses the use of non-thermal gelling dip-molding compositions of some hydroxyalkyl methyl celluloses in aqueous solvents. The pins must be kept in rotation for more than half an hour to obtain capsules with a regular shape.
U.S. Pat. No. 4,001,211 discloses improved thermogelling compositions based on a blend of methyl cellulose (MC) and hydroxypropyl methyl cellulose (HPMC).
However, the more recent patent publication WO 2008/050209 A1 discloses that the compositions and processes described above did not make it possible to obtain high-performance manufacturing of hard capsules both with regard to speed, dissolution properties and with regard to overall quality. It further discusses that capsules manufactured by a combination of HPMC with gelling agents have very poor visual quality and dissolution properties since they are sensitive to cations and to pH.
To overcome the disadvantages of the prior art, WO 2008/050209 suggests the use of an aqueous composition for the manufacture of hard capsules which comprises, in an aqueous solvent, 15-25% by weight, based on the total weight of the aqueous composition, of a hydroxypropyl methyl cellulose having a methoxy content of 27.0-30.0% (w/w), a hydroxypropoxy content of 4.0-7.5% (w/w) and a viscosity of 3.5-6.0 cPs as a 2% weight solution in water at 20° C. The use of this type of hydroxypropyl methyl cellulose provides advantages in the manufacture of capsules, compared to other hydroxypropyl methyl celluloses; aqueous solutions of the disclosed hydroxypropyl methyl cellulose have a lower gelation temperature than hydroxypropyl methyl celluloses having a methoxy content of 28.0-30.0% (w/w), a hydroxypropoxy content of 7.0-12% (w/w) and a corresponding viscosity. In the dip coating process for preparing capsules, it is common practice to heat the aqueous solution of the hydroxypropyl methyl cellulose to a temperature which is only a few degrees Celsius below its gelation temperature before pins are dipped into the aqueous solution of the hydroxypropyl methyl cellulose. Accordingly, a high gelation temperature is not desirable because this requires an unduly high amount of time and energy to heat the aqueous solution of the hydroxypropyl methyl cellulose. Unfortunately, even the gelation temperature of the hydroxypropyl methyl cellulose disclosed in WO 2008/050209 is still higher than desired by many capsule manufacturers. Moreover, hydroxyalkyl methylcelluloses are known to have a low storage modulus, compared to methyl cellulose. Hydroxyalkyl methylcelluloses which exhibit a low storage modulus do not form strong gels. High concentrations are needed to form even weak gels (Hague, A; Richardson, R. K.; Morris, E. R., Gidley, M. J and Caswell, D. C in Carbohydrate Polymers 22 (1993) p. 175; and Hague, A. and Morris, E. R. in Carbohydrate Polymers 22 (1993) p. 161). For example, at the same concentration of 2 wt.-%, at elevated temperatures the maximum storage modulus of a METHOCEL™ K4M HPMC is typically less than about 100 Pa, whereas that of a METHOCEL™ A4M methylcellulose is typically above about 1000 Pa. It is concluded that the hydroxyalkyl substituents inhibit intermolecular associations.
Accordingly, one object of the present invention is to provide novel cellulose ethers which are useful for producing capsules or coatings for dosage forms.
A preferred object of the present invention is to provide novel cellulose ethers which have a lower gelation temperature in aqueous solutions than known hydroxyalkyl methyl celluloses of the same viscosity and concentration in aqueous solutions.
Moreover, another preferred object of the present invention is to provide novel cellulose ethers which have a higher storage modulus than known hydroxyalkyl methylcelluloses.